Azodicarboxylic acids alcohol inversion

An example of an alcohol activation method is the Mitsunobu reaction. This reaction is performed by slow addition of the seco-acid alcohol to a mixture of diethyl azodicarboxylate (DEAD) and PPhs in toluene or THF. In the mechanism, the key intermediate is an alkoxyphosphonium cation, which is formed by DEAD and PPhs in situ. The macrolactone is formed by an intramolecular Sn2 reaction of this intermediate via an attack of the carboxylate moiety and therefore the reaction proceeds with inversion of the configuration at C-co. 

The corresponding 3a-hydroxy lactone 42 was synthesized from 68 using the Mitsunobu procedure (diethyl azodicarboxylate/triphenylphosphine/formic acid) for inversion of the hydroxy function in position 3.73 The resulting 3oc-formyloxy ester 73, upon hydrolysis afforded the 3a-alcohol 74. Asymmetric dihydroxylation of 74 yielded 24-epityphasterol (75) as the main product. Baeyer-Villiger oxidation of 75 led to 2-deoxy-24-epibrassinolide (42) and its isomeric lactone 76 in a 1 0.6 ratio.74... 

Esterification ofttUylic alcohols. Esterification of allylic alcohols with benzoic acid using triphenylphosphine and diethyl azodicarboxylate proceeds with inversion and without allylic rearrangement. ... 

Thiolesters. These esters are easily obtained by addition of an alcohol and then t h iolacetic acid to the preformed adduct of P(C6H 5)3 and diisopropyl azodicarboxylate in THF (equation I). The reaction is accompanied by inversion of configuration.5... 

Previously documented methods for menthol inversion under standard Mitsunobu conditions (benzoic acid, PPha, diethyl azodicarboxylate) result in low yields4 (27%). More effective methods have been reported using extended reaction periods in refluxing toluene via a formic acid/N,N -dicyclohexylcarbodiimide-mediated transformation5 (20-92 hr, 80%). For hindered alcohols in general, representative methods for inverting alcohol stereochemistry necessitate conversion of the alcohol to... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

This method is unusually mild, using neutral conditions and low temperatures (20 °C and less). It tolerates a number of functional groups in the components (e.g. acetals, esters, alkenes, etc.)- The alcohol, the carboxylic acid and triphenylphosphine are treated dropwise in an inert solvent (dichloromethane, THF, ether) with diethyl azodicarboxylate (DEAD). The ester is formed rapidly. However, tedious chromatography is frequently required to remove the by-products, triphenylphosphane oxide and hydrazo ester. The main value of the reaction lies in the clean inversion of configuration at a secondary carbinol center and in its selectivity towards primary hydroxy groups (vide infra). Inversions are usually performed with benzoic or p-nitrobenzoic acid. The benzoates are purified and saponified with aqueous base to furnish the inverted alcohols in overall yields of ca. 50%. Elimination is the main side reaction. Thus, from (44) 75% of the desired Sn2 product (45) is formed, along with 25% of the elimination product (46) (equation 19). The mechanism of the reaction has been clarified to the point that betaine (47) is the pri-... 

In the Mitsunobu reaction, a chiral 2° alcohol and a carboxylic acid are converted to an ester with clean inversion at the electrophilic C. The reaction requires PI13P and Et02CN=NC02Et (diethyl azodicarboxylate, DEAD). It is usually carried out by adding DEAD slowly to a mixture of the alcohol, PI13P, and the nucleophile in its protonated form. 

Mitsunobu et al. [46] reported an efficient macrolactonization using diethyl azodicarboxylate (DEAD) and Ph3P. In the case of (o-hydroxy acids having a secondary alcohol, this cyclization takes place with inversion of the configuration of the alcohol. In the total synthesis of latrunculin A (82) and B, the Mitsunobu reaction was used for the macrolactonization of the seco-acid 81 with inversion of the secondary alcohol [47]. 

Esterification.—An alternative to the well-known azodicarboxylate-PhsP esterification procedure has dimethyl mesoxalate as proton acceptor. Yields of esters of benzoic acid are quite good (50—86%), and the reaction results in complete configurational inversion of the alcohol component. Isocyanides have also been shown to be useful dehydrating reagents in this type of reaction. Esterification of acids with one equivalent of an alcohol can be achieved by prior reaction of the acid with 2-halopyridinium salts. cf. refs. 134—140). An overall conversion of amines into acetates and benzoates (Scheme 29) involves conversion... 

The Mitsunobu reaction, discovered by Oyo Mitsunobu (1934-2003) in 1967, is one of the most important among modern synthetic reactions. It allows the replacement of the OH group of primary and secondary alcohols with a variety of nucleophiles, with clean inversion of stereochemistry and under mild conditions. The key reagents are triphenylphosphine and a dialkyl azodicarboxylate the latter is very often diethyl azodicarboxylate (DEAD). In addition, a key requirement is that the nucleophile should be acidic (for reasons you ll see below) carboxylic acids, phenols, thiols, imides, and activated carbon acids are all appropriate nucleophiles. 

Condensation of alcohols and acidic components (NuH) on treatment with dialkyl azodicarboxylates and trialkyl- or triarylphosphines occurring primarily with inversion of configuration via the proposed intermediary oxyphosphonium salts ... 

Another interesting example of an inversion reaction is the Mitsunobu reaction, which displaces a hydroxyl with a carboxylate group. Reaction of a chiral alcohol with triphenylphosphine and diethyl azodicarboxylate (PhsP, DEAD) in the presence of a carboxylic acid results in the formation of a good leaving group followed by the Sn2 replacement of that group by the carboxylate nucleophile to give an ester product with an inverted stereochemistry. 

Allylic Alcohols. Conversion of alcohols into their benzoates by reaction with benzoic acid, triphenylphosphine and diethyl azodicarboxylate is known to proceed with inversion (see also above) at the alcohol centre. This process has been extended... 

Tosylate Formation with Inversion of Configuration. Alkyl tosylates can be formed directly from secondary alcohol functionality with retention of carbon stereochemistry by treatment withp-Toluenesulfonyl Chloride and Pyridine. However, conversion of an alcohol to the corresponding tosylate of opposite stereochemistry typically requires a minimum of three steps. For example, inversion of the stereocenter with benzoic acid under Mitsunobu reaction conditions, hydrolysis of the resulting ester, and finally conventional tosylation of the alcohol, provides an attractive route for this transformation. A similar route, the inversion of a secondary alcohol directly with p-TsOH, Diethyl Azodicarboxylate (DEAD), and Triphenylphosphine, does not produce the desired tosylate product. ... 

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